ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2426A>G (p.Glu809Gly) (rs397507201)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164846 SCV000215529 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-07 criteria provided, single submitter clinical testing The p.E809G variant (also known as c.2426A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 2426. The glutamic acid at codon 809 is replaced by glycine, an amino acid with similar properties. This alteration was reported in one individual with breast cancer diagnosed at age 39 (Darooei M et al. Tumour Biol. 2017 Feb;39:1010428317694303). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001086610 SCV000260562 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589185 SCV000698951 uncertain significance not provided 2016-05-09 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2426A>G (p.Glu809Gly) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome. This variant was found in 8/121344 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.0004849 (8/16498). This frequency is about 0.5 times of the estimated maximal allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a rare functional polymorphism found primarily in the populations of South Asian origin. Multiple clinical diagnostic laboratories have classified this variant as VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. It has been reported in two samples from patients affected with stomach cancer in COSMIC, one without confirmation of somatic status. Due to the sufficient clinical information and lack of functional studies, the variant has been classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Health, Inc RCV000164846 SCV000903581 likely benign Hereditary cancer-predisposing syndrome 2017-05-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589185 SCV001470160 likely benign not provided 2019-10-22 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031049 SCV000053643 uncertain significance Breast-ovarian cancer, familial 1 2009-12-26 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000504369 SCV000591385 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Glu809Gly variant was not identified in the literature, but was identified in dbSNP (ID: rs397507201) “with uncertain significance allele”, the COSMIC database in one sample, and the ClinVar database where it was classified with “Uncertain significance” by the Sharing Reports Clinical Project (derived from Myriad reports). The variant was not identified in any control populations, including the Exome Variant Server ESP project, the Exome Aggregation Consortium (ExAC) database, 1000 Genomes project, or HAPMAP populations. The variant was also not identified in any other databases searched, including the HGMD, UMD, LOVD and BIC databases. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Glu809 residue conserved across most mammals but is not conserved in lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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